Adeno-Associated Viral Vectors in Neuroscience Research

Adeno-associated viral vectors (AAVs) are increasingly useful preclinical tools in neuroscience research studies for interrogating cellular and neurocircuit functions and mapping brain connectivity. Clinically, AAVs have for transformative research and therapeutics in the neurosciences.

AAVs

AAVs are small, 4.7-kb, linear, single-stranded DNA (ssDNA) viruses in the parvovirus family that can infect multiple tissue types. Among types of commonly used viruses in neuroscience, AAVs can, similar to lentiviruses, infect both quiescent non-dividing cells, such as neurons, as well as dividing cells, whereas retroviruses only infect dividing cells. Additionally, AAV integration into the host genome can be prevented by removing Rep and Cap genes from plasmids. It has been reported that there are more than ten AAV serotypes applicable to the nervous system: 1, 3, 5, 6, 8, 9, PHP.B, PHP.eB, PHP.S, DJ, Retro, rh10, etc. Different serotypes have different infection efficiency and spreading ability in different parts of the nervous system, and the appropriate serotype is related to whether the gene can achieve efficient and stable expression, and even to the final Therefore, it is important to select the appropriate AAV serotype by combining the characteristics of the labeled cells and each AAV serotype.

Preclinical Use of AAVs in Neuroscience Research

Circuit Identification and Classification

Neuronal circuits are currently defined by many factors, such as location, connectivity, and cell type. To perform anatomical analyses of circuit nodes and comprehend these circuit topographies, a common goal is to utilize a viral vector that transduces a neuronal population of interest and expresses a fluorescent protein to visualize the target. Serotype 2 (AAV2) has a natural tropism for neurons and is the most commonly used and characterized serotype. AAV2 vectors encoding fluorescent proteins have been instrumental in mapping connectivity between brain regions in animal models. For example, the Allen Mouse Brain Connectivity Atlas project has utilized AAV2-EGFP vectors for tracing the axonal connections between multiple brain regions in the mouse brain. Many other laboratories also use similar techniques to map numerous cell types and neurocircuits in not only mice, but in many other species as well.

Fig. 1 Mapping axonal projections in the whole mouse brain. (Haggerty, et al., 2019)

Circuit Manipulation

Not only are AAVs an extremely flexible, efficient, and reliable tool for transducing reporters into specific nodes of circuits to understand the topography of neural circuits, but the ability to package elements into them beyond fluorescent reporters is truly where they have revolutionized neuroscience research. AAVs have also been useful tools for "tagging" neurons. Tagging techniques are useful for identifying recorded neurons in vivo, assessing neuronal network activation following completion of behavioral sequences or a specific in vivo treatment, or for post hoc isolation of activated cells for genetic or proteomic analyses.

Other AAV Functions

Beyond manipulating neuronal firing and sampling neuronal activity, AAVs have been incredibly useful tools for exploring the role of specific gene products within specific cell types within specific nodes in neuronal function and behavior.

Conclusion

AAVs have been truly transformative for basic neuroscience research, allowing for great advances in our understanding of brain connectivity, cellular function (including neurons and glia), and the roles of specific molecules and cell types in complex animal behaviors. As preclinical studies continue to provide more powerful AAV vectors for transducing specific cell types in the nervous system and more advanced methodologies for easier delivery of AAVs to the CNS, these findings from basic research have increasing translational potential for the development of novel therapeutics.

Reference:

Haggerty, D. L.; et al. Adeno-Associated Viral Vectors in Neuroscience Research. Mol Ther Methods Clin Dev. 2019 Nov 26;17: 69-82.

* For research use only. Not intended for any clinical use.

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